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Invasive cribriform and intraductal carcinoma (CR/IDC) is associated with adverse outcome of prostate cancer patients. The aim of this study was to determine the molecular aberrations associated with CR/IDC in primary prostate cancer, focusing on genomic instability and somatic copy number alterations (CNA).
Böttcher et al BMC Cancer (2018) 18:8 DOI 10.1186/s12885-017-3976-z RESEARCH ARTICLE Open Access Cribriform and intraductal prostate cancer are associated with increased genomic instability and distinct genomic alterations René Böttcher1†, Charlotte F Kweldam2†, Julie Livingstone3, Emilie Lalonde3,4, Takafumi N Yamaguchi3, Vincent Huang3, Fouad Yousif3, Michael Fraser5, Robert G Bristow4,5,6, Theodorus van der Kwast7, Paul C Boutros3,4,8†, Guido Jenster1† and Geert J L H van Leenders2*† Abstract Background: Invasive cribriform and intraductal carcinoma (CR/IDC) is associated with adverse outcome of prostate cancer patients The aim of this study was to determine the molecular aberrations associated with CR/IDC in primary prostate cancer, focusing on genomic instability and somatic copy number alterations (CNA) Methods: Whole-slide images of The Cancer Genome Atlas Project (TCGA, N = 260) and the Canadian Prostate Cancer Genome Network (CPC-GENE, N = 199) radical prostatectomy datasets were reviewed for Gleason score (GS) and presence of CR/IDC Genomic instability was assessed by calculating the percentage of genome altered (PGA) Somatic copy number alterations (CNA) were determined using Fisher-Boschloo tests and logistic regression Primary analysis were performed on TCGA (N = 260) as discovery and CPC-GENE (N = 199) as validation set Results: CR/IDC growth was present in 80/260 (31%) TCGA and 76/199 (38%) CPC-GENE cases Patients with CR/IDC and ≥ GS had significantly higher PGA than men without this pattern in both TCGA (2.2 fold; p = 0.0003) and CPC-GENE (1.7 fold; p = 0.004) cohorts CR/IDC growth was associated with deletions of 8p, 16q, 10q23, 13q22, 17p13, 21q22, and amplification of 8q24 CNAs comprised a total of 1299 gene deletions and 369 amplifications in the TCGA dataset, of which 474 and 328 events were independently validated, respectively Several of the affected genes were known to be associated with aggressive prostate cancer such as loss of PTEN, CDH1, BCAR1 and gain of MYC Point mutations in TP53, SPOP and FOXA1were also associated with CR/IDC, but occurred less frequently than CNAs Conclusions: CR/IDC growth is associated with increased genomic instability clustering to genetic regions involved in aggressive prostate cancer Therefore, CR/IDC is a pathologic substrate for progressive molecular tumour derangement Keywords: Cribriform, Intraductal carcinoma, Prostate cancer, Copy number alteration, Aggressive disease, Genomic instability Background Prostate cancer is heterogeneous regarding its pathologic features, genetic background and clinical outcome Clinicaldecision making mostly depends upon serum Prostate Specific Antigen (PSA) level, clinical tumour stage, and pathologic biopsy Gleason score (GS) – a grading system based on architectural tumour patterns [1] While patients * Correspondence: g.vanleenders@erasmusmc.nl † Equal contributors Department of Pathology, Erasmus University Medical Center, Josephine Nefkens Institute building, Be-222, P.O Box 2040, Rotterdam 3000 CA, The Netherlands Full list of author information is available at the end of the article with the lowest GS ≤6 (WHO/ISUP group 1) have an excellent patient outcome, those with the highest GS 9–10 (WHO/ISUP group 5) have the worst [1, 2] The clinical outcome of GS + = (WHO/ISUP group 2) prostate cancer patients is variable Improving risk assessment in this subgroup of patients is of clinical relevance as biopsy GS + = is an important threshold for active treatment Recent studies have indicated that, among Gleason grade growth patterns, cribriform growth is associated with worse clinical outcome [3–6] In recent years the clinical relevance of intraductal carcinoma of the prostate (IDC) – a malignant epithelial © The Author(s) 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated Böttcher et al BMC Cancer (2018) 18:8 proliferation filling and extending pre-existent glands – has been acknowledged Although not included in the Gleason grading system, IDC has been associated with high GS, advanced tumour stage, biochemical relapse and distant metastasis [7–12] IDC often mimics invasive cribriform carcinoma, requiring basal cell immunohistochemistry for their distinction Recently, our group has shown that patients with cribriform and/or intraductal carcinoma (CR/IDC), have significantly worse diseasespecific survival probabilities than those without, regardless of GS [13] Furthermore, patients with focal CR/IDC have similar outcome as men with extensive CR/IDC, indicating that the mere presence of this growth pattern is an adverse feature [13, 14] Although the number of mutational events in prostate cancer is relatively low, copy number alterations (CNAs) are significantly more frequent [15–24] Several studies have developed molecular prognostic signatures, showing that indolent tumours have relatively few CNAs in contrast to large-scale CNAs in highgrade or metastatic tumours [16, 17, 25, 26] However, both the intra- and inter-tumour heterogeneity pose significant challenges for personalizing treatment in patients with prostate cancer [27–29] For instance, GS prostate cancers harbour a wide range of CNA burden varying between